Molecular and functional mechanisms of bile acid TUDCA and physical exercise in attenuating sarcopenia in senescent mice: Involvement of autophagic pathways.

Abstract

The increase in life expectancy, together with the drop in the birth rate in recent decades, has drastically altered the age structure of the world population. Aging is closely related to the slow and progressive loss of skeletal muscle mass and strength, determinants of sarcopenia. An intrinsic characteristic of senile muscle is the loss of proteostasis, related to the accumulation of dysfunctional and damaged proteins and organelles, resulting from a reduction in the activation of autophagy. Defects in autophagic processes are responsible, for example, for the accumulation of dysfunctional mitochondria, which can aggravate the oxidative stress process, affecting the homeostasis of muscle tissue. Among the most used therapeutic strategies is physical training, which has been shown to be capable of attenuating or even reversing the process of muscular atrophy during aging. Numerous benefits of training in senile individuals have already been reported, such as the restoration of mitochondrial function, increased satellite cell functionality, reduced inflammation, and improved insulin sensitivity in skeletal muscle. Furthermore, although pharmacological strategies for the treatment of sarcopenia are little explored, in this study we highlight TUDCA, an endogenous bile acid that has shown great efficiency in the treatment of various metabolic dysfunctions. Unpublished data point to a beneficial potential of TUDCA in alleviating sarcopenia, since senile mice treated with TUDCA have greater muscle weight and strength, as well as a reduction in inflammation and an increase in the activation of protein synthesis pathways in the muscle. These findings highlight that both the performance of physical activities and the administration of TUDCA have the potential to modulate the signaling of important pathways for maintaining muscle tissue. Thus, this project aims to investigate the functional and molecular mechanisms involved in the action of TUDCA on the restoration of autophagy to improve muscle tissue homeostasis, as well as to investigate whether a combined intervention, the treatment with TUDCA associated with resistance physical training would have effects beneficial in alleviating sarcopenia in senile mice. For this, senile male C57BL/6 mice (18 months) will be used and will undergo treatment with TUDCA (intraperitoneal route) and chronic resistance training (4 weeks). In these animals, functional and molecular aspects of skeletal muscle will be evaluated, such as muscle strength, mitochondrial respiration capacity, inflammation, and regulation of anabolic and autophagic pathways, using techniques such as histology, high-resolution respirometry, RNA-Seq, western blot, and RT-PCR. This work may contribute to a better understanding of the effects of TUDCA bile acid and physical exercise on skeletal muscle maintenance, acting as potential tools for the treatment of sarcopenia related to aging.